During an inspection of your firm located in Bronshoj, Denmark, on May 1 through May 4, 2006, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures various blood gas analyzers, transcutaneous p02/pC02/Sp02/Pulse Monitors, Membrane Accessory Kits 904-308, 904-892, 904-206, and 904-260, related accessories, controls, and calibration solutions. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.

Further, during an inspection of your associated firm, Radiometer America, Inc., located in Westlake, Ohio, on March 10, 2006, through May 25, 2006, an investigator from the FDA determined that this firm distributes your above products in the United States, and conducted 42 Field Actions (device corrections/updates) from January 2005 to May 2006 involving many of these products. Records were collected at this firm regarding your firm's investigations and corrective actions taken regarding these Field Actions.

These inspections revealed that these devices are adulterated within the meaning of section 501(h) of the Act (21 U.S.C. § 351(h)), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (C.F.R.), Part 820. We received a response from Mr. Kirsten Rono, Director of Regulatory Affairs dated May 18, 2006, concerning our investigator's observation noted on the Form FDA 483, List of Inspectional Observations, that was issued to you. We address this response below in relation to one of the noted violations. These violations include, but are not limited to, the following:

1. Failure to establish and maintain adequate procedures for implementing corrective and preventative action to identify actions needed to correct and prevent recurrence of nonconforming product and other quality problems, as required by 21 CFR 820.100(a)(3). For example:

a. Your firm opened Corrective and Preventative Action (CAPA) 5761 on September 9, 2005, to correct and prevent the excessive rejection of batches 224 and 225 model TCM4/40/400 blood gas analyzer electrodes for not meeting their specification for 02 drift during in-process testing. Your firm determined that the two batches of electrodes' component membrane material, and the lot of membrane material that the electrode material came from, likewise did not meet the specification for 02 drift. Your firm was not able to determine the cause of the 02 drift for the membrane material, and, hence, your firm has not identified a corrective and preventive action needed to correct and prevent recurrence of received nonconforming membrane material. Your firm's action of testing a limited number of samples of the material upon receipt does not address the unidentified cause of the material nonconformity.

b. Your firm determined that when the TCM4 Transcutaneous p02/pC02 Monitoring System is turned on and the boot process begins, the device stops right after the memory count and will not proceed further because of lack of compatibility between the device's Main CPU PC Board and one vendor's [redacted] CompactFlash Card. Your firm exchanged the Simple Tech Card with another vendor's card that did not experience the problem, but your firm did not identify any system corrections or preventive action to the design process, device testing process, or supplier control process to ensure this type of problem/failure does not occur in other manufactured finished devices.

c. Your firm determined that Capillary end caps component for part #s 904-39 and 904-453, an accessory for ABL Series Blood Gas Analyzers, would leak blood from capillary tubes used to transfer blood to the blood gas analyzers, because the end caps did not meet dimensional specifications. Your firm determined that your supplier's production process was changed in that the injection process was faster, which caused defects in the caps upon cooling. Your firm's Corrective Action was to have the supplier make changes on the form (mold) which produces the end caps. However, your firm did not identify any system corrections or preventive action to ensure this type of problem/failure does not occur in other accessory components, such as actions involving purchasing controls or component receiving acceptance. Further, FDA could find no evidence that your firm reviewed and approved the supplier's changed molding process which requires process validation or revalidation.

2. Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventative action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, it appears that both the frequency and number of electrodes rejected during electrode production testing for batches 226 through 247 after CAPA 5761 was implemented, have increased compared to the levels for batches 193 through 223 before CAPA 5671 was implemented. Your firm did not evaluate the nonconformities (rejects) after CAPA 5761 to determine the relationship of the failures prior to CAPA 5761.

We have reviewed your firm's response and have concluded that it is inadequate. Your firm states that it will now examine finished electrodes containing the membrane material that are each tested during production to see if any are rejected for 02 drift because of membrane material problems, and if so, your firm will conduct a further investigation. Your firm stated it will do this over an 8 month period looking at 1000 electrodes. Your firm's response is inadequate as follows:

A. The response does not define how your firm plans to perform its analysis of rejected electrodes.

B. The response does not address what will be done if the 02 drift fails for a reason other than membrane material problems.

Your firm states that it recently implemented new CAPA procedures, which it attached, so that future situations similar to the one described in the FDA 483 observation will be avoided. Your firm's response is inadequate as follows:

C. The response did not include the referenced CAR Form needed to evaluate the CAPA procedures.

D. The response did not include any evidence of training to the new CAPA procedures.

E. Your firm's CAPA procedures do not verify or validate a CAPA action until after it is implemented, and there is no statement in the procedures or reference to the CAR Form that finished products will be quarantined or held until the verification or validation ensures that the CAPA action is effective and does not adversely affect the finished device.

You should take prompt action to correct the violation(s) addressed in this letter. Failure to promptly correct these violation(s) may result in regulatory action, which may include detaining your devices without physical examination upon entry into the United States until the corrections are completed. (Section 801(a) of the Act (21 U.S.C. § 381(a)) Also, U.S. federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.

Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violation(s), or similar violation(s), from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. If the documentation is not in English, please provide a translation to facilitate our review.

Your response should be sent to: William C. MacFarland, Chief, Orthopedic, Physical Medicine and Anesthesiology Devices, Division of Enforcement B, Office of Compliance, Center for Devices and Radiological Health, Food and Drug Administration, 2098 Gaither Road, HFZ-343, Rockville, MD 20850. If you have any questions about the content of this letter please contact: William F. Defibaugh at (240)-276-0298 or fax 240-276-0325.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violation(s), and take prompt actions to correct the violation(s) and to bring your products into compliance.